Apolipoprotein E (apoE) is synthesized and secreted by a wide variety of mammalian cells and a number of hypotheses have been developed regarding the potential functions of apoE synthesized in extrahepatic tissues. The macrophage was the first extrahepatic cell type in which apoE synthesis was reported and a great deal of information has been developed characterizing the regulation of apoE synthesis in these cells. We have been primarily interested in further exploring the mechanisms for the regulation of macrophage apoE production. In this application, we propose experiments designed to a) define the molecular mechanism for the induction of apoE gene transcription which i) accompanies cholesterol loading of macrophages; ii) accompanies differentiation of monocytes to macrophages; and b) examine post-transcriptional and post-translational regulation of apoE in macrophages and specifically, to determine how this step is modulated in response to differentiation and extracellular lipids. Our laboratory has been involved in making important basic observations for each of the experimental directions outlined above. Macrophages are a major source of apoE in extrahepatic tissues. A role for apoE has been established in participating in tissue lipid transport as well as modulating the growth, phenotype and differentiated function of a diverse group of extrahepatic cells (e.g. lymphocytes, steroidogenic cells, and mesenchymal cells). Understanding the regulation of apoE production in macrophages could provide major insights into understanding the pathophysiology of disease processes in which macrophages play a key role, for example, atherosclerosis.